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A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.


ABSTRACT: Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G>A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G>A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.

SUBMITTER: Nadarajah N 

PROVIDER: S-EPMC6121331 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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A Novel Splice-Site Mutation in <i>VEGFC</i> Is Associated with Congenital Primary Lymphoedema of Gordon.

Nadarajah Noeline N   Schulte Dörte D   McConnell Vivienne V   Martin-Almedina Silvia S   Karapouliou Christina C   Mortimer Peter S PS   Jeffery Steve S   Schulte-Merker Stefan S   Gordon Kristiana K   Mansour Sahar S   Ostergaard Pia P  

International journal of molecular sciences 20180801 8


Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. <i>VEGFC</i>, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral cong  ...[more]

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